Drug Discov Ther. 2010;4(5):380-387.

Comparative evaluation of ketoconazole-β-cyclodextrin systems prepared by coprecipitation and kneading.

Marzouk MA, Kassem AA, Samy AM, Amer RI


Ketoconazole (KZ), an imidazole antifungal, was formulated into inclusion complexes via coprecipitation and kneading with β-cyclodextrin (β-CD) as a carrier in 1:1 and 1:2 drug to carrier ratios. The KZ-β-CD solid complexes were characterized by X-ray diffraction and differential scanning calorimetry (DSC). The diffraction pattern of the pure drug revealed the drug to be highly crystalline in nature, as indicated by numerous distinctive peaks. The lack of numerous distinctive peaks of the drug in KZ-β-CD complexes prepared by the two methods revealed that a large number of the drug molecules were dissolved in a solid-state carrier matrix with an amorphous structure. The thermograms of the KZ-β-CD complexes showed a strong reduction in the intensity and broadening of drug peaks somewhat in both kneading and coprecipitation systems, suggesting that the drug is monomolecularly dispersed in the β-CD cavity. The prepared tablets of KZ-β-CD solid complexes prepared by the two methods were evaluated for their quality control testing, and an in vitro release study and the results of quality control complied with pharmacopeial requirements and the release profiles indicated complete drug release after 30 min. The kinetic parameters obtained from release data were analyzed in order to explain the mechanism of drug release and revealed non-Fickian transport. Accelerated stability testing at 35°C, 45°C, and 55°C and at 75% relative humidity was carried out for six months and revealed somewhat stable systems as indicated by a t90 of about 2 years for both KZ-β-CD systems. A microbiological in vitro assay of KZ from the prepared tablets was performed using Candida albicans as a model fungus, and KZ had improved microbiological activity when administered as an inclusion complex with β-CD. The results confirmed the benefit of using CDs as a useful tool to enhance the dissolution and hence bioavailability of poorly water-soluble drugs by forming solubilizing systems when exposed to gastrointestinal fluid.

KEYWORDS: Ketoconazole, β-cyclodextrin inclusion complex, spectroscopic study, tablets, quality control, in vitro release, stability, microbiological study

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